Mutant DLX 3 disrupts odontoblast polarization and dentin formation
Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 ( DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant DLX3 (MT-DLX3...
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| Veröffentlicht in: | Developmental biology 2010-08, Vol.344 (2), p.682-692 |
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| description | Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (
DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant
DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 Col1A1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker caspase-3 were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of
Runx2,
Wnt 10A, and
TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased
TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism.
In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology. |
| doi_str_mv | 10.1016/j.ydbio.2010.05.499 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2945701</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S001216061000802X</els_id><sourcerecordid>754893979</sourcerecordid><originalsourceid>FETCH-LOGICAL-c556t-6e0fe3ad1dc0e17ea4840caad41849bc594d5bc0bdaf474370b5b939e2e2943e3</originalsourceid><addsrcrecordid>eNp9kM9LHDEUx0NpqVvbv0CQufU025dJMjM5WCirtsKKFwVvIZO8sVlmk22SEexf3-haqZeeHrz3_fH4EHJEYUmBtl82ywc7uLBsoGxALLmUb8iCghS1aPntW7IAoE1NW2gPyIeUNgDA-p69JwcNCApN0y_I6nLO2ufqdH1bscq6FOddTlWwwecwTDrlahcmHd1vnV3wlfa2suiz89UY4vZp-ZG8G_WU8NPzPCQ352fXqx_1-ur7xerbujZCtLluEUZk2lJrAGmHmvccjNaW057LwQjJrRgMDFaPvOOsg0EMkklssJGcITskX_e5u3nYojXljagntYtuq-ODCtqp1xfvfqq7cK-KXXRAS8Dn54AYfs2Ystq6ZHCatMcwJ9UJ3pfCThYl2ytNDClFHF9aKKhH-mqjnuirR_oKhCr0i-v43wdfPH9xF8HJXoAF073DqJJx6A1aF9FkZYP7b8EfO8iZTw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>754893979</pqid></control><display><type>article</type><title>Mutant DLX 3 disrupts odontoblast polarization and dentin formation</title><source>MEDLINE</source><source>ScienceDirect Journals (5 years ago - present)</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Choi, S.J. ; Song, I.S. ; Feng, J.Q. ; Gao, T. ; Haruyama, N. ; Gautam, P. ; Robey, P.G. ; Hart, Thomas C.</creator><creatorcontrib>Choi, S.J. ; Song, I.S. ; Feng, J.Q. ; Gao, T. ; Haruyama, N. ; Gautam, P. ; Robey, P.G. ; Hart, Thomas C.</creatorcontrib><description>Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (
DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant
DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 Col1A1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker caspase-3 were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of
Runx2,
Wnt 10A, and
TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased
TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism.
In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology.</description><identifier>ISSN: 0012-1606</identifier><identifier>EISSN: 1095-564X</identifier><identifier>DOI: 10.1016/j.ydbio.2010.05.499</identifier><identifier>PMID: 20510228</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Bone and Bones - metabolism ; Caspase 3 - analysis ; Caspase 3 - genetics ; Caspase 3 - metabolism ; Dentin - metabolism ; Dentin mineralization ; DLX3 ; Ectodermal Dysplasia - genetics ; Ectodermal Dysplasia - metabolism ; Humans ; Male ; Mice ; Mice, Transgenic ; Odontoblasts - chemistry ; Odontoblasts - metabolism ; Odontogenesis - genetics ; Sequence Deletion - genetics ; Taurodontism, TDO, odontoblast polarization, apoptosis, TBC1D19 ; Tooth - metabolism ; Transgenic mouse</subject><ispartof>Developmental biology, 2010-08, Vol.344 (2), p.682-692</ispartof><rights>2010</rights><rights>Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c556t-6e0fe3ad1dc0e17ea4840caad41849bc594d5bc0bdaf474370b5b939e2e2943e3</citedby><cites>FETCH-LOGICAL-c556t-6e0fe3ad1dc0e17ea4840caad41849bc594d5bc0bdaf474370b5b939e2e2943e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ydbio.2010.05.499$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20510228$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Choi, S.J.</creatorcontrib><creatorcontrib>Song, I.S.</creatorcontrib><creatorcontrib>Feng, J.Q.</creatorcontrib><creatorcontrib>Gao, T.</creatorcontrib><creatorcontrib>Haruyama, N.</creatorcontrib><creatorcontrib>Gautam, P.</creatorcontrib><creatorcontrib>Robey, P.G.</creatorcontrib><creatorcontrib>Hart, Thomas C.</creatorcontrib><title>Mutant DLX 3 disrupts odontoblast polarization and dentin formation</title><title>Developmental biology</title><addtitle>Dev Biol</addtitle><description>Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (
DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant
DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 Col1A1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker caspase-3 were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of
Runx2,
Wnt 10A, and
TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased
TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism.
In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology.</description><subject>Animals</subject><subject>Bone and Bones - metabolism</subject><subject>Caspase 3 - analysis</subject><subject>Caspase 3 - genetics</subject><subject>Caspase 3 - metabolism</subject><subject>Dentin - metabolism</subject><subject>Dentin mineralization</subject><subject>DLX3</subject><subject>Ectodermal Dysplasia - genetics</subject><subject>Ectodermal Dysplasia - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Odontoblasts - chemistry</subject><subject>Odontoblasts - metabolism</subject><subject>Odontogenesis - genetics</subject><subject>Sequence Deletion - genetics</subject><subject>Taurodontism, TDO, odontoblast polarization, apoptosis, TBC1D19</subject><subject>Tooth - metabolism</subject><subject>Transgenic mouse</subject><issn>0012-1606</issn><issn>1095-564X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM9LHDEUx0NpqVvbv0CQufU025dJMjM5WCirtsKKFwVvIZO8sVlmk22SEexf3-haqZeeHrz3_fH4EHJEYUmBtl82ywc7uLBsoGxALLmUb8iCghS1aPntW7IAoE1NW2gPyIeUNgDA-p69JwcNCApN0y_I6nLO2ufqdH1bscq6FOddTlWwwecwTDrlahcmHd1vnV3wlfa2suiz89UY4vZp-ZG8G_WU8NPzPCQ352fXqx_1-ur7xerbujZCtLluEUZk2lJrAGmHmvccjNaW057LwQjJrRgMDFaPvOOsg0EMkklssJGcITskX_e5u3nYojXljagntYtuq-ODCtqp1xfvfqq7cK-KXXRAS8Dn54AYfs2Ystq6ZHCatMcwJ9UJ3pfCThYl2ytNDClFHF9aKKhH-mqjnuirR_oKhCr0i-v43wdfPH9xF8HJXoAF073DqJJx6A1aF9FkZYP7b8EfO8iZTw</recordid><startdate>20100815</startdate><enddate>20100815</enddate><creator>Choi, S.J.</creator><creator>Song, I.S.</creator><creator>Feng, J.Q.</creator><creator>Gao, T.</creator><creator>Haruyama, N.</creator><creator>Gautam, P.</creator><creator>Robey, P.G.</creator><creator>Hart, Thomas C.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>5PM</scope></search><sort><creationdate>20100815</creationdate><title>Mutant DLX 3 disrupts odontoblast polarization and dentin formation</title><author>Choi, S.J. ; Song, I.S. ; Feng, J.Q. ; Gao, T. ; Haruyama, N. ; Gautam, P. ; Robey, P.G. ; Hart, Thomas C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c556t-6e0fe3ad1dc0e17ea4840caad41849bc594d5bc0bdaf474370b5b939e2e2943e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Bone and Bones - metabolism</topic><topic>Caspase 3 - analysis</topic><topic>Caspase 3 - genetics</topic><topic>Caspase 3 - metabolism</topic><topic>Dentin - metabolism</topic><topic>Dentin mineralization</topic><topic>DLX3</topic><topic>Ectodermal Dysplasia - genetics</topic><topic>Ectodermal Dysplasia - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Odontoblasts - chemistry</topic><topic>Odontoblasts - metabolism</topic><topic>Odontogenesis - genetics</topic><topic>Sequence Deletion - genetics</topic><topic>Taurodontism, TDO, odontoblast polarization, apoptosis, TBC1D19</topic><topic>Tooth - metabolism</topic><topic>Transgenic mouse</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Choi, S.J.</creatorcontrib><creatorcontrib>Song, I.S.</creatorcontrib><creatorcontrib>Feng, J.Q.</creatorcontrib><creatorcontrib>Gao, T.</creatorcontrib><creatorcontrib>Haruyama, N.</creatorcontrib><creatorcontrib>Gautam, P.</creatorcontrib><creatorcontrib>Robey, P.G.</creatorcontrib><creatorcontrib>Hart, Thomas C.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Developmental biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Choi, S.J.</au><au>Song, I.S.</au><au>Feng, J.Q.</au><au>Gao, T.</au><au>Haruyama, N.</au><au>Gautam, P.</au><au>Robey, P.G.</au><au>Hart, Thomas C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutant DLX 3 disrupts odontoblast polarization and dentin formation</atitle><jtitle>Developmental biology</jtitle><addtitle>Dev Biol</addtitle><date>2010-08-15</date><risdate>2010</risdate><volume>344</volume><issue>2</issue><spage>682</spage><epage>692</epage><pages>682-692</pages><issn>0012-1606</issn><eissn>1095-564X</eissn><abstract>Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (
DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant
DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 Col1A1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker caspase-3 were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of
Runx2,
Wnt 10A, and
TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased
TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism.
In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20510228</pmid><doi>10.1016/j.ydbio.2010.05.499</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present); EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Bone and Bones - metabolism Caspase 3 - analysis Caspase 3 - genetics Caspase 3 - metabolism Dentin - metabolism Dentin mineralization DLX3 Ectodermal Dysplasia - genetics Ectodermal Dysplasia - metabolism Humans Male Mice Mice, Transgenic Odontoblasts - chemistry Odontoblasts - metabolism Odontogenesis - genetics Sequence Deletion - genetics Taurodontism, TDO, odontoblast polarization, apoptosis, TBC1D19 Tooth - metabolism Transgenic mouse |
| title | Mutant DLX 3 disrupts odontoblast polarization and dentin formation |
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